OBJECTIVES: Atrial fibrillation (AF) is an arrhythmia that increases stroke risk. Left atrial appendage (LAA) occlusion with a LAA closure device is the first non-pharmacologic strategy to undergo randomized, warfarin-controlled trials. It has demonstrated non-inferiority to the current standard, warfarin, for stroke and systemic embolism prevention. The objective of this study was to evaluate the cost-effectiveness of LAA closure relative to chronic warfarin therapy for stroke prevention in AF patients at elevated stroke risk.  METHODS: A Markov model was constructed from the payer perspective assuming a cohort of AF patients aged 65 with a CHADS score≥2 at model entry. Clinical inputs were obtained from published trials. Utilities were obtained from published studies assessing quality-of-life in AF patients. Costs were obtained from published literature. Using quarterly cycles, the model was run over the patients’ remaining lifetime summing total costs and total quality-adjusted-life-years (QALYs) for each arm.  RESULTS: Total QALYs gained for the warfarin and device arms were 11.58 and 11.76, respectively. Total costs for the warfarin and device arms were $84,100 and $89,400, respectively. The base-case ICER for LAA closure compared to warfarin was $29,600/QALY. The model was most sensitive to underlying rates of stroke and intracranial hemorrhage (ICH) and the relative risk of stroke and ICH in the device arm compared to warfarin. It was relatively robust to costs and utilities. Monte Carlo simulation with 10,000 iterations demonstrated LAA closure was cost-effective in 50% and 54% of simulations at thresholds of $50,000/QALY and $100,000/QALY. CONCLUSIONS: Though not yet available in the US, trial data suggests LAA closure is an option for anticoagulant-eligible AF patients. It is estimated to be cost-effective at previously acceptable willingness-to-pay thresholds, but uncertainty around the ICER suggests a need for more precise parameter estimates. It remains a novel mechanism to improve outcomes in undertreated AF patients.